Currently, the treatment of diabetes, both type 1 diabetes and type 2 diabetes, relies to an increasing extent on the so-called intensive insulin treatment. According to this regimen, the patients are treated with multiple daily insulin injections comprising one or two daily injections of a long acting insulin to cover the basal insulin requirement supplemented by bolus injections of a rapid acting insulin to cover the insulin requirement related to meals.
Long acting insulin compositions are well known in the art. Thus, one main type of long acting insulin compositions comprises injectable aqueous suspensions of insulin crystals or amorphous insulin. In these compositions, the insulin compounds utilized typically are protamine insulin, zinc insulin or protamine zinc insulin.
Certain drawbacks are associated with the use of insulin suspensions. Thus, in order to secure an accurate dosing, the insulin particles must be suspended homogeneously by gentle shaking before a defined volume of the suspension is withdrawn from a vial or expelled from a cartridge. Also, for the storage of insulin suspensions, the temperature must be kept within more narrow limits than for insulin solutions in order to avoid lump formation or coagulation.
While it was earlier believed that protamines were non-immunogenic, it has now turned out that protamines can be immunogenic in man and that their use for medical purposes may lead to formation of antibodies. Also, evidence has been found that the protamine-insulin complex is itself immunogenic. Therefore, with some patients the use of long acting insulin compositions containing protamines must be avoided.
Another type of long acting insulin compositions are solutions having a pH value below physiological pH from which the insulin will precipitate because of the rise in the pH value when the solution is injected. A drawback with these solutions is that the particle size distribution of the precipitate formed in the tissue on injection, and thus the release profile of the medication, depends on the blood flow at the injection site and other parameters in a somewhat unpredictable manner. A further drawback is that the solid particles of the insulin may act as a local irritant causing inflammation of the tissue at the site of injection.
International patent application published under number WO 2005/012347 (Novo Nordisk A/S) concerns insulin derivatives which have a sidechain attached to either the α-amino group of the N-terminal amino acid residue of the B-chain or the ε-amino group of a Lys residue present in the B chain.
International patent application No. EP2006/050593 (Novo Nordisk A/S) discloses insulin derivatives having an aromatic group in the side chain.
Patent application no. EP2006/050594 (Novo Nordisk A/S), disclose insulin derivatives having a PEG in the side chain.
Other insulin derivatives are disclosed in JP laid-open patent application No. 1-254699 (Kodama Co., Ltd.) and WO 95/07931 (Novo Nordisk A/S).
However, there is still a need for insulin having a more prolonged profile of action than the insulin derivatives known up till now.